Eight years ago I had the idea of combining ustekinumab and vedolizumab after anti-TNF failure in Crohn's disease. Each drug alone only went so far. Would the two together do better? At UEG Week, Remo Panaccione presented the first data on ABBV-466, AbbVie's combination of risankizumab with trosunilimab, a new anti-α4β7 antibody. Trosunilimab isn't vedolizumab, and it isn't a biosimilar of it. It's a new human antibody that AbbVie first developed for HIV research. In their lab work it binds α4β7 about 13 times more tightly than a comparator built from published sequences. So α4β7 is back as a target in Crohn's disease, this time as a partner for IL-23 blockade. AbbVie's tissue data, not yet published, show why that might work. In CD tissue, the IL-23 receptor and α4β7 sit on mostly different cells. Risankizumab alone leaves most of the gut-homing cells untouched. The trial was part of the TARGET-CD platform study. It took 300 adults with moderate to severe CD, and three quarters had already failed an advanced therapy. They were randomised to risankizumab, trosunilimab or both (ABBV-466). Endoscopic remission at week 12 was 30% on the combination, against 21% and 18% on each drug alone. By week 24 it was 41% against 22% and 20%. The combination almost doubled the rate and was still climbing, while each drug alone had levelled off. By week 24, more than half on the combination had an endoscopic response. The pattern held in people who had already failed an advanced therapy: 40% against 21% and 13% at week 24. Early transcriptomics from small biopsy subsets look interesting too. Epithelial repair and barrier genes rose by week 12, and tissue repair, nerve growth and vitamin transport genes by week 24, mainly on the combination. Safety looked similar across the three arms. It's phase 2a and open-label. The only p-value is nominal, at week 24. Clinical remission wasn't presented, and the doses haven't been disclosed. But AbbVie is already running a blinded phase 2 platform study in around 2,000 people with CD and UC, which includes ABBV-466 at two doses. The harder test is under way. I should have run that study eight years ago. Of course, no one would have funded it back then!

Preparing a long post on advanced combination therapy to cover the evidence, strategies, trials, commercial pressures and of course clinical need. It is a fascinating topic with lots to cover.